Abstract
BackgroundHigh inflammation status despite an absence of known infection characterizes a subpopulation of people with schizophrenia who suffer from more severe cognitive deficits, less cortical grey matter, and worse neuropathology. Transcripts encoding factors upstream of nuclear factor kappa B (NF-κB), a major transcriptional activator for the synthesis of pro-inflammatory cytokines, are increased in the frontal cortex in schizophrenia compared to controls. However, the extent to which these changes are disease-specific, restricted to those with schizophrenia and high-neuroinflammatory status, or caused by loss of a key NF-κB inhibitor (HIVEP2) found in schizophrenia brain, has not been tested.MethodsPost-mortem prefrontal cortex samples were assessed in 141 human brains (69 controls and 72 schizophrenia) and 13 brains of wild-type mice and mice lacking HIVEP2 (6 wild-type, 7 knockout mice). Gene expression of pro-inflammatory cytokines and acute phase protein SERPINA3 was used to categorize high and low neuroinflammation biotype groups in human samples via cluster analysis. Expression of 18 canonical and non-canonical NF-κB pathway genes was assessed by qPCR in human and mouse tissue.ResultsIn humans, we found non-canonical upstream activators of NF-κB were generally elevated in individuals with neuroinflammation regardless of diagnosis, supporting NF-κB activation in both controls and people with schizophrenia when cytokine mRNAs are high. However, high neuroinflammation schizophrenia patients had weaker (or absent) transcriptional increases of several canonical upstream activators of NF-κB as compared to the high neuroinflammation controls. HIVEP2 mRNA reduction was specific to patients with schizophrenia who also had high neuroinflammatory status, and we also found decreases in NF-κB transcripts typically induced by activated microglia in mice lacking HIVEP2.ConclusionsCollectively, our results show that high cortical expression of pro-inflammatory cytokines and low cortical expression of HIVEP2 in a subset of people with schizophrenia is associated with a relatively weak NF-κB transcriptional signature compared to non-schizophrenic controls with high cytokine expression. We speculate that this comparatively milder NF-κB induction may reflect schizophrenia-specific suppression possibly related to HIVEP2 deficiency in the cortex.
Highlights
The transcription factor nuclear factor kappa B (NF-κB) is a critical regulator of immune responses and controls the expression of various pro-inflammatory cytokines and acute phase proteins [1, 2] that are increased in the brain in people with schizophrenia [3,4,5,6,7,8,9]
Collectively, our results show that high cortical expression of pro-inflammatory cytokines and low cortical expression of HIVEP2 in a subset of people with schizophrenia is associated with a relatively weak Nuclear factor kappa B (NF-κB) transcriptional signature compared to non-schizophrenic controls with high cytokine expression
Gene expression of members of 3 key processes are reportedly elevated in schizophrenia compared to controls: (1) receptors that initiate NF-κB signalling (interleukin-1 receptor type 1 (IL1R1), tumor necrosis factor receptor superfamily member 1A (TNFR1), toll-like receptor 4 (TLR4), cluster of differentiation 40 (CD40), lymphotoxin receptor beta (LTβR), and TNFR superfamily member 1B (TNFR2)); (2) subunits that form NF-κB dimers (proto-oncogene Proto-oncogene RelA (RelA) (RelA), proto-oncogene c-Rel, NF-κB subunit 1 (NFKB1), and NF-κB subunit 2 (NFKB2)); and (3) kinases that induce their translocation into the nucleus (inhibitor of NF-κB kinase subunit alpha (IKKα), IKK beta (IKKβ), and NF-κB-inducing kinase (NIK))
Summary
The transcription factor nuclear factor kappa B (NF-κB) is a critical regulator of immune responses and controls the expression of various pro-inflammatory cytokines and acute phase proteins [1, 2] that are increased in the brain in people with schizophrenia [3,4,5,6,7,8,9]. Volk et al found increased expression of NF-κB inhibitor alpha (IκBα), which is upregulated by NF-κB activation itself in a negative feedback mechanism [16] Another NF-κB inhibitor, human immunodeficiency virus type 1 enhancer binding protein 2 (HIVEP2) is decreased in schizophrenia cortex compared to controls [14]. These findings suggest that NF-κB is overactive in the cortex in people with schizophrenia and drives neuroinflammation in patients that may be causally relevant to their symptomatology. The extent to which these changes are disease-specific, restricted to those with schizophrenia and high-neuroinflammatory status, or caused by loss of a key NF-κB inhibitor (HIVEP2) found in schizophrenia brain, has not been tested
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